18F-FDG PET and PET/CT for the evaluation of gastric signet ring cell carcinoma: a systematic review

Background In the last years, 18F-fluorodeoxyglucose PET/computed tomography (18F-FDG PET/CT) has demonstrated its utility for the evaluation of gastric cancer; however, considering some histotypes such as gastric signet ring cell carcinoma (GSRCC) the results are limited. The aim of this review is to analyze the diagnostic performance of 18F-FDG PET and PET/CT for the assessment of GSRCC. Methods A wide literature search of the PubMed/MEDLINE, Scopus, Embase and Cochrane library databases was made to find relevant published articles about the diagnostic performance of 18F-FDG PET or PET/CT for the evaluation of GSRCC. Results The comprehensive computer literature search revealed 179 articles. On reviewing the titles and abstracts, 162 articles were excluded because the reported data were not within the field of interest. Nine studies were included in the review and references were also screened for additional articles. Finally, 26 articles were selected and retrieved in full-text version. Conclusion Despite some limitations affect our review, GSRCC seems to have low 18F-FDG uptake, and therefore 18F-FDG PET or PET/CT reveals impaired sensitivity for its evaluation. However, a correlation between 18F-FDG uptake and some clinico-pathologic features (such as stage, depth of invasion, size and presence of nodal metastasis) has been demonstrated. Besides, a possible prognostic role of PET/CT features is starting to emerge.


Introduction
Gastric cancer is one of the most common and aggressive cancer worldwide. Despite the decrease in incidence in the last decades, the survival rate remains low because the clinical presentation is often absent or nonspecific [1,2].
Gastric cancer can be histologically divided according to a different classification. World Health Organization (WHO) is one of the most used such as Lauren classification that divides gastric cancer mainly into intestinal and diffuse cancer, comprising gastric signet ring cell cancer (GSRCC) and other types [3].
Complete surgical removal of the primitive tumor with nodal dissection is a pivotal part of the treatment of disease. However, recurrence is often present, ranging from 22 to 48% of the cases [4].
Accurate and early staging of the disease is fundamental for treatment planning and nowadays a complete workup includes computed tomography (CT), gastroscopy and laparoscopy [1]. In the last years, 18 F-fluorodeoxyglucose PET/computed tomography ( 18 F-FDG PET/CT) has increased its role for staging and restaging of disease, because of its ability to provide both anatomic and functional information. Its use has been widely demonstrated especially in treatment planning [5].
Stomach evaluation with 18 F-FDG PET/CT may be challenging due to the risk of having heterogeneous gastric uptake distribution owing to different inflammatory and physiologic states. Besides, diabetic patients, especially in therapy with oral hypoglycemic drugs, may present an increased tracer uptake in the bowel, which affects and limits the evaluation of the scan in the gastrointestinal tract [6,7].
Despite the proven usefulness of 18 F-FDG PET/CT for the evaluation of patients affected by gastric cancer, its role remains controversial given its low general sensitivity [8]. In particular, gastric cancer seems to be non 18 F-FDG-avid in a high percentage of cases, up to 53% as reported in the literature, and impaired 18 F-FDG uptake is particularly evident when GSRCC is present [1]. The aim of this systematic review is to analyze the performance of 18 F-FDG PET or PET/CT for the assessment of GSRCC.
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
No beginning date limit was applied to the search and it was updated until 31 October 2020. Only articles in the English language were considered; preclinical studies, conference proceedings, reviews and editorials were excluded. To expand our search, the references of the retrieved articles were also screened for additional papers.

Study selection
Two researchers (F.D. and D.A.) independently reviewed the titles and the abstracts of the retrieved articles. The same two researchers then independently reviewed the full-text version of the remaining articles to determine their eligibility for inclusion. The studies with less than eight patients affected by GSRCC were conventionally excluded from the review due to the low sample analyzed. The quality assessment, including the risk of bias and applicability concerns, was carried out using Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 evaluation [9].

Data abstraction
For each included study, data concerning the basic study were collected (author names, year of publication, country of origin and type of study) and PET device used, number of patients evaluated and number of patients affected by GSRCC. The main findings of the articles included in this review are reported in the Results.
In general, the quality assessment using QUADAS-2 evaluation underlined a low risk of bias (Fig. 2a) and low problem regarding applicability concerns (Fig. 2b).

F-FDG avidity and diagnostic accuracy of PET and PET/CT
Several studies have reported that 18 F-FDG PET and PET/CT imaging has impaired accuracy for the evaluation of GSRCC, compared to other gastric cancer histotypes.
In particular, the sensitivity and specificity of 18 F-FDG imaging are higher for non-GSRCC compared to GSRCC [10,12,18,22,31]. Furthermore, a higher rate of false-negative scans is described in patients affected by GSRCC [10,14,26,34]. In general, the criteria used to define PET scan positivity or negativity were comparable among the studies considered in the review and consisted of visual and semiquantitative evaluation for most of the studies. PET scan was considered positive when an increased FDG uptake higher than background activity in the surrounding tissue and blood pool was present; positron imaging was also compared to other imaging modalities or hystopathologic evidence when available.
Regarding diagnostic accuracy of 18 F-FDG PET/CT for the evaluation of GSRCC, the data included in the review are very heterogeneous. The detection rate of PET/CT ranges from 14 to 98% of the cases, depending on hystopatologic classification used in each study. Furthermore, the sensitivity varies from 15 to 63% and the specificity from 60 to 100% considering only GSRCC, but only small amounts of the studies clearly report these informations.
Moreover, the lower 18 F-FDG uptake of GSRCC has been underlined by many studies and standardized uptake value (SUV) is usually lower compared to other gastric cancer subtypes [10,11,18,22,25,28]. Significant differences in terms of the detection rate and SUV values between intestinal and nonintestinal gastric cancer have also been reported such as a strong correlation between the presence of mucus and impaired 18 F-FDG uptake, with the presence of higher SUV in nonmucus-containing tumors [15,20,28]. These findings are also true when comparing GRSCC and poorly-differentiated gastric cancer to well-differentiated forms [11,32]. Moreover, diffuse gastric cancer presented low positivity of primary lesions compared to other histotypes [32]. Interestingly, some clinicopathologic parameters such as stage, depth of invasion, size, presence of nodal metastasis and lymphovascular invasion are demonstrated to be correlated with the degree of 18 F-FDG uptake [16]. Despite the similarity of SUV between different gastric cancer histotypes, diffuse-type tumors tend to have larger primary tumor than other types [14]. Higher SUVmax, SUV mean , total lesion glycolysis (TLG) and metabolic tumor volume (MTV) have also been reported for well-differentiated and moderately-differentiated cancer compared to poorly-differentiated and GSRCC cancer [29].
Otherwise, some studies report no differences in terms of 18 F-FDG uptake and sensitivity between GSRCC and non-GSRCC cancer and surprisingly in some cases GSRCC demonstrates higher SUV [27,30,33,35].
As primary lesions, lymph node localization of GSRCC tends to be less 18 F-FDG avid than other gastric cancer nodal metastasis and therefore PET imaging has impaired sensitivity [11,14,21,26].

Correlation of 18 F-FDG uptake and glucose transporter-1 or human epidermal growth factor receptor 2 expression
Correlation between 18 F-FDG uptake and glucose transporter-1 (GLUT-1) expression in gastric cancer has been reported. In particular, GSRCC has significantly lower expression of this transporter than other gastric cancer histotypes, resulting in impaired 18 F-FDG uptake and detection [4,17,19].
Expression of human epidermal growth factor receptor 2 (HER2) in GSRCC has also been studied in the past. In particular, a lower HER2 expression rate in GSRCC compared to well-differentiated and moderately-differentiated cancer has been demonstrated. Moreover, this difference is not present when considering SRCC and poorly-differentiated forms of gastric cancer. [25,29]. Furthermore, PET/CT parameters such as SUV max , SUV mean , TLG and MTV are significantly higher in HER2 positive patients [29]. In contrast to what was previously reported, increased GLUT-1 expression for nonintestinal cancers has been also reported in literature [30].

Prognostic value of 18 F-FDG PET/CT
18 F-FDG PET/CT is recently starting to emerge as a promising imaging method of prognostic utility in GSRCC. When considering all gastric cancer together, the presence of GSRCC or lower SUV max are correlated with shorter overall survival (OS) [23,29]. However, when considering GSRCC or diffuse histology, patients with higher SUV max tend to have more relapse, shorter relapse free survival, lower cancer-specific survival rate and shorter OS [16,22]. Moreover, the absence of GSRCC, higher SUV max and higher TLG were associated with pathologic complete response [24]. However, these insights are not clearly supported by other findings when evaluating the role of PET/CT in predicting the recurrence of GSRCC [20].
As previously mentioned, GSRCC is classified as nonintestinal, diffuse and mucus-containing cancer [3]. Different uptake between intestinal and nonintestinal gastric cancer have been described by Stahl et al., [28] despite the fact that nonintestinal tumor were higher in grade than intestinal types. Moreover, a strong correlation between the presence of mucus and impaired 18 F-FDG uptake was also reported. Similar findings were also confirmed by other authors [14,15,18,22,23,31]. Kim et al., [14] reported that despite the similarity of SUV between different gastric cancer histotypes, diffuse-type tumors had significantly larger primary tumor compared to other types. Partially in contrast, in their article, Chon et al., [22] reported that the degree of correlation between SUV max and size of primary lesion was relatively weak for patients with GSRCC or diffuse histology. 18 F-FDG uptake, expressed as SUV max , may be related with some clinical and histologic features, such as depth of invasion, size, presence of nodal metastasis and lymphovascular invasion, proposed by Pak et al., [16]. Moreover, they reported that patients with higher SUV max had larger tumors, more total gastrectomies and higher stages compared to the group of lower SUV max . In this context, Harada et al., [24] showed that high SUV max and TLG were associated with the absence of GSRCC.
Nodal localizations of GSRCC, especially if regional, tends to be less 18 F-FDG avid than other gastric tumor nodal metastasis resulting in impaired sensitivity for PET and PET/CT imaging [11,12,14,21,26]. For example, Kim et al., [14], underlined reduced sensitivity and SUV for GSRCC nodal metastasis and furthermore univariate analysis reported GSRCC and SUV to be significant variables for nodal metastasis detection. However, multivariate analysis confirmed only SUV as an independent predictive variable. In a recent article, Arslan et al., [26] demonstrated that SUV max of positive regional lymph Copyright © 2021 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Utility of 18F-FDG imaging for GSRCC assessment Dondi et al. 1297 (continued) nodes were significantly lower for GSRCC. Interestingly, this difference was not confirmed when considering distant lymph nodes as also suggested by Smyth et al., [32] reporting that in patients with diffuse cancer, metastatic disease was more likely to be detected by laparoscopy than PET/CT.
It is known that the GLUT-1 overexpression plays a major role for 18 F-FDG uptake by cancer cells [36]. In this context, studies about the expression of this transporter in GSRCC have been performed reporting in general reduced GLUT1 presence [13,17,19]. Yamada et al., [13] reported that tracer uptake and detection rate on 18 F-FDG PET/CT differed depending on GLUT-1 expression between the GSRCC and other subtypes of gastric cancer. When applying multiple regression analysis, GLUT-1 expression was the most influential factor for predicting the degree of 18 F-FDG uptake. Choi et al., [19] reported that, in GSRCC, group of membranous pattern of GLUT-1 staining had significantly higher SUV max than group of cytoplasmic pattern. Significant differences were also reported in tracer uptake when comparing depth of invasion, extent of nodal metastasis and stage, where higher stage demonstrated increased SUV max .
Also, anti-HER2 antibodies are starting to emerge as a tool for gastric cancer treatment [37] and therefore, given the ability of HER2 cancer status to predict response to treatment, correlation between 18 F-FDG uptake and receptor expression has been researched through the years. In general, GSRCC demonstrated lower HER2 expression compared to other gastric cancer [25,29]. In this context, Park et al., [29], reported that SUV max , SUV mean , TLG and MTV were significantly higher in HER2 positive patients. Interestingly, the authors also reported that in negative HER2 patients, no correlation between prognosis and PET/CT parameters was highlighted.
In the last years, general implications on the prognostic value of 18 F-FDG PET/CT in GSRCC are starting to arise. Pak et al., [16] reported that for GSRCC patients with higher SUV max had more relapse, shorter relapsefree survival, lower cancer-specific survival rate and lower OS. Univariate analysis demonstrated tumor nodes and metastases stage, type of gastrectomy and SUV max as significant variables for the prediction of survival. More recently, Lee et al., [20] evaluated the possible role of 18 F-FDG PET/CT in predicting recurrence after curative surgical resection, reporting only marginal significance was present for GRSCC when considering a negative scan as predictive of longer recurrence-free survival. The difference was significant when considering other gastric cancer subtypes. Similarly, Charalampakis et al., [23] underlined that patients with lower SUV and presence of GSRCC had the tendency to shorter OS. Moreover, Harada et al., [24] reported that in absence of GSRCC, SUV max and TLG were associated with pathologic complete response. Lastly, Chon et al., [22] reported that in presence of diffuse or GSRCC, higher SUV max was correlated to shorter disease-free survival and OS.
A singular study was proposed by Herrmann et al., [18] when comparing 18   CT for the staging of gastric cancer. 18 F-FLT demonstrated lower uptake in GSRCC compared to other gastric cancer subtypes but higher sensitivity compared to 18 F-FDG. The authors than suggested 18 F-FLT as a promising tool for the evaluation of the particular aggressive histologic type of gastric cancer, such as GSRCC.
As previously mentioned, some works are partially in contrast to the findings reported. For example, Mochiki et al., [27] reported that histology of primary gastric cancer did not significantly influence the detection of disease on PET imaging. Similar results were obtained by Hur et al., [33]. Higher uptake of 18 F-FDG by GSRCC compared to other gastric cancer was otherwise reported by Takebayashi et al., [30]. Surprisingly, the authors reported increased GLUT-1 expression for nonintestinal cancers. Similar results were also underlined by Kim et al., [35] reporting that adenocarcinoma had lower accuracy than GSRCC. In general, the low percentage of GSRCC presented in these studies is suggested by the authors as a possible explanation for these results.

Conclusion
In conclusion, 18 F-FDG PET or PET/CT demonstrated impaired diagnostic accuracy for the evaluation of primary GSRCC and nodal localization compared to other gastric cancer histotypes. Interestingly, the uptake and the main semiquantitative parameters (such as SUV) are generally lower for GSRCC. Reduced GLUT-1 and HER2 expression is also present in GSRCC. Lastly, a possible prognostic role of 8 F-FDG PET/CT features is starting to emerge.